Abstract Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection in infants and young children, however no vaccine is currently available. The overall objective of this grant is to develop optimal live attenuated RSV vaccine candidate(s). The significance of this P01 is that it brings together a multidisciplinary group of investigators to leverage a novel observation that infants with severe RSV disease display a pattern of inadequate (or suppressed) immune responses. The grant will simultaneously attack this problem on multiple fronts by developing a vaccine with increased immunogenicity, attenuating the virus in a novel, `tunable' way, improving its yield in cell culture to improve vaccine production, and using gene expression and new antibody detection tools for analysis of the immune response in order to predict vaccine effectiveness and safety. These candidates will be tested first in vitro in primary well differentiated human airway epithelial cultures. Vaccine candidates with the desired characteristics will be selected for testing in vivo in cotton rats for their attenuation and their ability to induce a `safe' host response (similar to natural mild RSV disease in infants), and potent neutralizing antibodies to RSV. Combination mutants will be recycled through this system, resulting in the selection of one optimal vaccine candidate and rank order of excellent backups. By integrating the host response to RSV infection with modifications of the virus that improve these responses, the four projects of this P01 will synergize to develop an optimized live attenuated RSV vaccine candidate ready for testing in human primates and possibly clinical trials.